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Prenatal imaging findings in fetal Zika virus infection.

Abstract: The aim of this review is to report the most recent observations concerning intrauterine Zika virus (ZIKV) infection and associated neuroimaging.ZIKV outbreak in Brazil in 2015 was associated with an impressive registration of cases of congenital microcephaly in women with symptoms suggestive of ZIKV infection. Clinical and laboratory testing for ZIKV and hypothetic etiopathogenetic mechanisms are described. Diagnostic tests on blood, urine and amniotic fluid should be performed in all mothers with symptoms suggestive of intrauterine ZIKV infection. ZIKV causes multiple teratogenic malformations, mainly affecting the developing brain.Neuroimaging investigation contributes to the prenatal detection of microcephaly and other brain abnormalities in cases of intrauterine ZIKV infection. Neuroimaging is based antenatally on two-dimensional and three-dimensional ultrasound and fetal MRI, whereas computed tomography scan is performed postnatally. Although neuropathology associated with intrauterine ZIKV infection is characterized by nonspecific findings of brain disorder, reduced cortical gyration and white-matter hypomyelination or dysmyelination and cerebellar hypoplasia have been consistently observed in the majority of fetuses and newborns. Prenatal or postnatal genetic workup should be carried out to exclude cases of primary microcephaly. Follow-up should rely upon MRI and computed tomography scan as well as neuropediatrician to better define developmental outcome in survivors.

Pub.: 31 Jan '17, Pinned: 15 Feb '17

Testing for Zika Virus (ZIKV) Infection in Pregnancy: Key Concepts to Deal with an Emerging Epidemic.

Abstract: Zika virus (ZIKV) is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Following epidemics in Micronesia and French Polynesia during the past decade, more recent ZIKV infection outbreaks were first reported in South America as early as May of 2013, and spread to now 50 countries throughout the Americas. Although no other flavivirus has previously been known to cause major fetal malformations following perinatal infection, reports of a causal link between ZIKV and microcephaly, brain and ocular malformations, and fetal loss emerged from hard hit regions of Brazil by October 2015. Among the minority of infected women with symptoms, clinical manifestations of ZIKV infection may include fever, headache, arthralgia, myalgia and maculopapular rash; however, only one out of every four to five people who are infected have any symptoms. Thus, clinical symptom reporting is an ineffective screening tool for the relative risk assessment of ZIKV infection in the majority of patients. As previously occurred with other largely asymptomatic viral infections posing perinatal transmission risk (such as HIV or CMV), we must develop and implement rapid, sensitive, and specific screening and diagnostic testing for both viral detection and estimation of timing of exposure. Unfortunately, despite an unprecedented surge in attempts to rapidly advance perinatal clinical testing for a previously obscure arbovirus, there are several ongoing hindrances to molecular and sonographic based screening and diagnosis of congenital ZIKV infection. These include: (1) difficulty in estimating the timing of exposure for women living in endemic areas, and thus limited interpretability of IgM serologies; (2) cross-reaction of IgM serologies with other endemic flaviruses, such as dengue (DENV); (3) persistent viremia and viruria in pregnancy weeks to months after primary exposure; and (4) fetal brain malformations and anomalies preceding the sonographic detection of microcephaly. In this commentary, we discuss screening and diagnostic considerations which are grounded not only in the realities of current obstetrical practice in a largely global population, but in basic immunology and virology. We review recent epidemiologic data pertaining to risk of congenital ZIKV malformations based on trimester of exposure, and consider side by side with emerging data demonstrating replication of ZIKV in placental and fetal tissue throughout gestation. We discuss limitations to ultrasound based strategies which rely largely or solely on the detection of microcephaly, and provide alternative neurosonographic approaches for the detection of malformations which may precede or occur independent of a small head circumference. This expert review provides information that is of value for the: 1) obstetrician, maternal-fetal medicine specialist, midwife, patient and family in cases of suspected ZIKV infection; 2) reviews the methodology for laboratory testing to explore the presence of the virus and the immune response; 3) ultrasound based assessment of the fetus suspected to be exposed to ZIKV with particular emphasis on the central nervous system; and 4) identifies areas ready for development.

Pub.: 28 Jan '17, Pinned: 15 Feb '17

Zika virus targeting in the developing brain.

Abstract: Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems including microcephaly, cortical thinning and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a type 1 interferon response (IFNR(-/-)), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS, and may target different cells at different stages of brain development.Zika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested and initially targeted astrocytes throughout the brain. Infections of the retina were detected in all mice, and infection of CNS visual system nuclei in the brain were common. We find ZIKV can be transported axonally, thereby enhancing virus spread within the brain. These data suggest ZIKV infects multiple cell types within the brain and that astrocyte infection may play a more important role in initial infection than previously appreciated.

Pub.: 27 Jan '17, Pinned: 15 Feb '17

Use of Obstetric Practice Web Sites to Distribute Zika Virus Information to Pregnant Women During a Zika Virus Outbreak.

Abstract: To describe the current use of obstetric practice Web sites to disseminate Zika virus information to patients.Review of 913 randomly selected practice Web sites and associated social media accounts in January and August 2016.Obstetric practice Web sites and associated social media accounts, United States of America.N/A.Proportion of obstetric practice Web sites and linked social media accounts providing Zika virus information.Twenty-five percent and 35% of obstetric practice Web sites had information posted about Zika virus in January 2016 and August 2016, respectively. Between the 2 time points, the proportion of practices posting Zika virus content on Facebook and Twitter declined (Facebook: 15% in January, 9% in August; Twitter: 12% in January, 8% in August). In August, the most frequently observed Zika virus-related content themes were the use of insect repellent (14%) and travel advisories (14%). At both time points, practices affiliated with large university hospitals were more likely to have posted information on Zika virus than independent OB/GYN-only practices: January: odds ratio (OR) (95% confidence interval [CI]) = 5.68 (3.50-9.20); August: OR (95% CI) = 8.37 (5.31-13.17). Similarly, practices associated with nonuniversity hospitals were more likely to have posted information than independent OB/GYN-only practices: January: OR (95% CI) = 2.71 (1.88-3.92); August: OR (95% CI) = 6.75 (4.75-9.60).Obstetric care practices are not fully utilizing their practice Web sites to relay Zika virus information to their patients. Since practitioner-sponsored Web sites have the capacity to directly reach the populations at greatest risk for Zika virus complications, public health professionals should consider adapting their materials and provider outreach campaigns to more easily accommodate Web site-based information dissemination during this type of public health emergency. There must be greater recognition of the value information gains in the eyes of the patient when it is validated by their own provider, especially when that patient is part of the highest-risk population for a given emergency. Public health organizations should strive to minimize the burden it takes for providers to relay useful resources to patients in order to maximize the impact that those resources can have.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Pub.: 27 Jan '17, Pinned: 15 Feb '17

Epidemic Potential for Local Transmission of Zika Virus in 2015 and 2016 in Queensland, Australia.

Abstract: Zika virus could be transmitted in the state of Queensland, Australia, in parts of the state where the mosquito vectors are established.We assessed the epidemic potential of Zika in Queensland from January 2015 to August 2016, and estimate the epidemic potential from September to December 2016, by calculating the temperature-dependent relative vectorial capacity (rVc), based on empirical and estimated parameters.Through 2015, we estimated a rVc of 0.119, 0.152, 0.170, and 0.175, respectively in the major cities of Brisbane, Rockhampton, Cairns, and Townsville. From January to August 2016, the epidemic potential trend was similar to 2015, however the highest epidemic potential was in Cairns. During September to November 2016, the epidemic potential is consistently the highest in Cairns, followed by Townsville, Rockhampton and Brisbane. Then, from November to December 2016, Townsville has the highest estimated epidemic potential.We demonstrate using a vectorial capacity model that ZIKV could have been locally transmitted in Queensland, Australia during 2015 and 2016. ZIKV remains a threat to Australia for the upcoming summer, during the Brazilian Carnival season, when the abundance of vectors is relatively high. Understanding the epidemic potential of local ZIKV transmission will allow better management of threats to blood safety and assessment of public health risk.

Pub.: 27 Jan '17, Pinned: 03 Feb '17

Preventive and therapeutic challenges in combating Zika virus infection: are we getting any closer?

Abstract: The neuroteratogenic nature of Zika Virus (ZIKV) infection has converted what would have been a tropical disease into a global threat. Zika is transmitted vertically via infected placental cells especially in the first and second trimesters. In the developing central nervous system (CNS), ZIKV can infect and induce apoptosis of neural progenitor cells subsequently causing microcephaly as well as other neuronal complications in infants. Its ability to infect multiple cell types (placental, dermal, and neural) and increased environmental stability as compared to other flaviviruses (FVs) has broadened the transmission routes for ZIKV infection from vector-mediated to transmitted via body fluids. To further complicate the matters, it is genetically similar (about 40%) with the four serotypes of dengue virus (DENV), so much so that it can almost be called a fifth DENV serotype. This homology poses the risk of causing cross-reactive immune responses and subsequent antibody-dependent enhancement (ADE) of infection in case of secondary infections or for immunized individuals. All of these factors complicate the development of a single preventive vaccine candidate or a pharmacological intervention that will completely eliminate or cure ZIKV infection. We discuss all of these factors in detail in this review and conclude that a combinatorial approach including immunization and treatment might prove to be the winning strategy.

Pub.: 25 Jan '17, Pinned: 03 Feb '17

An integrated approach for the assessment of the Aedes aegypti and Aedes albopictus global spatial distribution, and determination of the zones susceptible to the development of Zika virus.

Abstract: The Zika virus, one of the new epidemic diseases, is reported to have affected millions of people in the past year. The suitable climate conditions of the areas where Zika virus has been reported, especially in areas with a high population density, are the main cause of the current outbreak and spread of the disease. Indeed, the suitable climatic conditions of certain territories constitute perfect breading nest for the propagation and outbreak of worldwide diseases. The main objective of this research is to analyze the global distribution and predicted areas of both mosquitoes Ae. aegypti and Ae. albopictus which are the main vectors of Zika virus. Physical (SRTM) and climatic variables (WorldClim) were used to obtain the susceptibility maps based on the optimum conditions for the development of these mosquitoes. The susceptibility model was developed using a Species Distribution Model - correlative model, namely the Maximum Entropy, that used as input the spatial references of both vectors (Dryad Digital Repository). The results show the most important classes of each independent variable used in assessing the presence of each species of mosquitoes and the areas susceptible to the presence of these vector species. It turns out that Ae. aegypti has greater global dispersion than the Ae. albopictus specie, although two common regions stand out as the most prone to the presence of both mosquito species (tropical and subtropical zones). The crossing of these areas of greater susceptibility with areas of greater population density (e.g. India, China, Se of USA and Brazil) shows some agreement, and these areas stand out due to the presence of several records of Zika virus (HealthMap Project). In this sense, through the intersection of susceptibility and human exposure the areas with increased risk of development and spread of Zika virus are pinpointed, suggesting that there may be a new outbreak of this virus in these places, if preventive measures are not adopted.

Pub.: 24 Jan '17, Pinned: 24 Jan '17

Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B.

Abstract: The endoplasmic reticulum (ER) is exploited by a number of diverse viruses during their infectious life cycles. Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), utilize the ER as a source of membranes to establish their replication organelles and to facilitate their assembly and eventual maturation along the secretory pathway. In order to maintain normal homeostasis, host cells have evolved highly efficient processes to dynamically regulate the ER, such as through reticulophagy, a selective form of autophagy that leads to ER degradation. Here, we identify the ER-localized reticulophagy receptor FAM134B as a host cell restriction factor for both DENV and ZIKV. We show that RNAi-mediated depletion of FAM134B significantly enhances both DENV and ZIKV replication at an early stage of the viral life cycle. Consistent with its role as an antiviral host factor, we found that several flaviviruses including DENV, ZIKV, and West Nile virus (WNV), utilize their NS3 virally-encoded proteases to directly cleave FAM134B at a single site within its reticulon homology domain (RHD). Mechanistically, we show that NS3-mediated cleavage of FAM134B blocks the formation of ER and viral protein-enriched autophagosomes, suggesting that the cleavage of FAM134B serves to specifically suppress the reticulophagy pathway. These findings thus point to an important role for FAM134B and reticulophagy in the regulation of flavivirus infection and suggest that these viruses specifically target these pathways to promote viral replication.

Pub.: 20 Jan '17, Pinned: 24 Jan '17

Reducing Unintended Pregnancies as a Strategy to Avert Zika-Related Microcephaly Births in the United States: A Simulation Study.

Abstract: Introduction There is increasing evidence that infection with the Zika virus (ZIKV) during pregnancy can lead to severe brain abnormalities in infants exposed in utero. The objective of our analysis was to estimate the contribution of enhanced contraception access to averting ZIKV-related microcephaly births in the United States, alone and in combination with another possible strategy, anti-ZIKV vaccination. Methods We used Monte Carlo sampling techniques (n = 100,000 simulations) to estimate the number of microcephaly births expected under strategies of enhanced contraception only, vaccination only, both enhanced contraception and vaccination, and status quo (no intervention). Enhanced contraceptive access was assumed to reduce unintended pregnancy rates by 46% and anti-ZIKV vaccination was assumed to be 90% effective. Plausible values for effectiveness of enhanced contraceptive access, ZIKV cumulative incidence, ZIKV-related microcephaly risk, and anti-ZIKV vaccination parameters were derived from the literature or best available knowledge. Results Enhanced contraceptive access alone reduced the median number of ZIKV-related microcephaly births by 16% (95% simulation interval: 5, 23), while the anti-ZIKV vaccine alone reduced these births by 9% (95% SI: 0, 18), 45% (95% SI: 36, 54), and 81% (95% SI: 71, 91), under conservative (10% vaccine uptake), moderate (50% vaccine uptake), and optimistic (90% vaccine uptake) scenarios, respectively. The reduction in ZIKV-related microcephaly births was always greater if both interventions were employed. Discussion Enhanced contraceptive access alone has the ability to produce a meaningful reduction in microcephaly births, and could provide an important adjuvant prevention strategy even following the development of a highly-effective anti-ZIKV vaccine.

Pub.: 20 Jan '17, Pinned: 24 Jan '17

Defining the Risk of Zika and Chikungunya Virus Transmission in Human Population Centers of the Eastern United States.

Abstract: The recent spread of mosquito-transmitted viruses and associated disease to the Americas motivates a new, data-driven evaluation of risk in temperate population centers. Temperate regions are generally expected to pose low risk for significant mosquito-borne disease; however, the spread of the Asian tiger mosquito (Aedes albopictus) across densely populated urban areas has established a new landscape of risk. We use a model informed by field data to assess the conditions likely to facilitate local transmission of chikungunya and Zika viruses from an infected traveler to Ae. albopictus and then to other humans in USA cities with variable human densities and seasonality. Mosquito-borne disease occurs when specific combinations of conditions maximize virus-to-mosquito and mosquito-to-human contact rates. We develop a mathematical model that captures the epidemiology and is informed by current data on vector ecology from urban sites. The model demonstrates that under specific but realistic conditions, fifty-percent of introductions by infectious travelers to a high human, high mosquito density city could initiate local transmission and 10% of the introductions could result in 100 or more people infected. Despite the propensity for Ae. albopictus to bite non-human vertebrates, we also demonstrate that local virus transmission and human outbreaks may occur when vectors feed from humans even just 40% of the time. Inclusion of human behavioral changes and mitigations were not incorporated into the models and would likely reduce predicted infections. This work demonstrates how a conditional series of non-average events can result in local arbovirus transmission and outbreaks of human disease, even in temperate cities.

Pub.: 18 Jan '17, Pinned: 24 Jan '17